2-(2-phenylethenyl) 1,3-benzodiazepine derivatives useful for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9073880-B2
Application number	US-201113976876-A
Country	US
Kind code	B2
Filing date	Dec 27, 2011
Priority date	Dec 27, 2010
Publication date	Jul 7, 2015
Grant date	Jul 7, 2015

Abstract

The present invention provides compounds of formula (1) acting as protein kinase (PK) and receptor kinase (RK) signaling modulators. The invention further provides methods of their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as anti-cancer agents for preventions and treatments of PK- and RK-related disorders, in particular cancer. (I) wherein A is H or CN; Z is S, SO or S0 2 ; X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 and Y 2 are each independently selected from H, halogen, alkyl, haloalkyl and OR 1 ; and Y 3 and Y 4 are each OR 1 , wherein each R 1 is independently H, C 1 -C 4 alkyl, acyl, —(CH 2 CH 2 0) n wherein n is an integer of 1 to 20, or a functional group that gives rise to hydroxyl upon hydrolysis.

First claim

What is claimed is:

1. A compound represented by the structure of formula 1:

wherein
A is H or CN;
Z is S, SO or SO 2 ;
X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 and Y 2 are each independently selected from H, halogen, alkyl, haloalkyl and OR 1 ; and
Y 3 and Y 4 are each OR 1 , wherein each R 1 is independently H, C 1 -C 4 alkyl, acyl, —(CH 2 CH 2 O) n wherein n is an integer of 1 to 20, or a functional group that gives rise to hydroxyl upon hydrolysis,
including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof.

2. A compound according to claim 1 , wherein A is H.

3. A compound according to claim 1 , wherein A is CN.

4. A compound according to claim 1 , wherein Z is S.

5. A compound according to claim 1 , wherein Z is SO 2 .

6. A compound according to claim 1 , wherein
at least one of X 1 , X 2 , X 3 , X 4 , Y 1 and Y 2 is a halogen; or
X 1 , X 2 , X 3 , and X 4 are each H or a halogen; or
Y 3 and Y 4 are each OH; or
Y 1 and Y 2 are each OH.

7. A compound according to claim 1 , wherein
A is H, Z is S, Y 3 and Y 4 are each OH, and X 1 is a halogen selected from Br and I; or
A is CN, Z is S, Y 3 and Y 4 are each OH, and X 1 is a halogen selected from Br and I; or
A is H, Z is S, Y 3 and Y 4 are each OH, and X 3 is a halogen selected from Br and I; or
A is H, Z is S, Y 3 and Y 4 are each OH, and X 2 is a halogen selected from Br and I; or
A is H, Z is S, Y 3 and Y 4 are each OH, and X 1 and X 4 are each a halogen selected from Br and I; or
A is H, Z is SO 2 , Y 3 and Y 4 are each OH, and X 1 is a halogen selected from Br and I; or
A is H, Z is SO 2 , Y 3 and Y 4 are each OH, and at least one of X 1 , X 2 , X 3 , X 4 , Y 1 and Y 2 is a halogen.

8. A compound according to claim 1 , wherein
X 2 is H; or
X 5 is H or alkyl.

9. A compound according to claim 1 , selected from the group consisting of:

10. A pharmaceutical composition comprising a therapeutically effective amount a compound according to claim 1 , and a pharmaceutically acceptable carrier or excipient.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , in combination with at least one other anti-cancer agent.

12. A method of inhibiting signal transduction mediated by a protein kinase (PK), comprising the step of contacting a cell comprising said PK with a compound according to claim 1 ; wherein the protein kinase is IGF-1R.

13. The method according to claim 12 , wherein the compound of formula (1) directly or indirectly interacts with, affects or inhibits said PK or a protein in said PK-mediated pathway; wherein the protein kinase is IGF-1R.

14. The method according to claim 13 , wherein the compound of formula (1) is an inhibitor of an insulin receptor or an insulin-like growth factor-1 receptor (IGF-1R), or wherein the compound of formula (1) directly or indirectly interacts with, affects or inhibits a substrate protein in the IGF-1R mediated pathway.

15. The method according to claim 14 , wherein the substrate protein is Insulin Receptor Substrate 1 (IRS1), Insulin Receptor Substrate 2 (IRS2), or a combination thereof, wherein said compound of formula (1) leads to any one or more of (i) dissociation of IRS1 or IRS2 from the cell membrane; (ii) phosphorylation of IRS1 or IRS2; or (iii) degradation of IRS1 or IRS2, in any order.

16. A method for treating an insulin-like growth factor I receptor (IGF-1R), an insulin receptor substrate 1 (IRS1) or an insulin receptor substrate 2 (IRS2) signaling related disorder in a subject, comprising the step of administering to the subject a compound according to claim 1 ; wherein the disorder is cancer.

17. A method of inhibiting proliferation of a cancer cell selected from the group consisting of melanoma, ovary, prostate, colon, multiple myeloma, and breast cancer cell comprising contacting the cell with a compound according to claim 1 .

18. A method of treating cancer selected from the group consisting of ovarian cancer, prostate cancer, breast cancer, skin cancer, melanoma, metastatic melanoma, colon cancer, lung cancer, pancreatic cancer, gastric cancer, bladder cancer, Ewing's sarcoma, osteosarcoma, glioblastoma, lymphoma, leukemia, multiple myeloma, head and neck cancer, brain cancer, kidney cancer, bone cancer, liver cancer, hepatocarcinoma and thyroid cancer in a subject comprising the step of administering to the subject a compound according to claim 1 .

Assignees

• Reuveni Hadas
• Levitzki Alexander
• Yissum Res Dev Co

Inventors

• Reuveni Hadas
• Levitzki Alexander

Classifications

• C07D279/08 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5415

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title